Pre-Mixed, Ready-To-Use Pharmaceutical Compositions

ABSTRACT

Provided herein are ready-to-use premixed pharmaceutical compositions of nicardipine or a pharmaceutically acceptable salt and methods for use in treating cardiovascular and cerebrovascular conditions.

1. CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/010,898 filed on Jun. 18, 2018, which is a continuation of Ser. No.15/159,495 filed on May 19, 2016, which is a continuation of U.S. patentapplication Ser. No. 12/977,965 filed on Dec. 23, 2019, now issued asU.S. Pat. No. 9,370,586, which is a continuation of U.S. patentapplication Ser. No. 12/645,169, filed on Dec. 22, 2009, now issued asU.S. Pat. No. 9,364,564, which is a continuation of U.S. patentapplication Ser. No. 12/407,557 filed on Mar. 19, 2019, now issued asU.S. Pat. No. 7,659,291, which is a divisional of U.S. patentapplication Ser. No. 11/788,076, filed on Apr. 18, 2007, now issued asU.S. Pat. No. 7,612,102, which claims benefit under 35 U.S.C. § 119(e)to U.S. Provisional application Serial No. 60/793,074, filed Apr. 18,2006, the contents of which are incorporated herein by reference.

2. BACKGROUND

Nicardipine hydrochloride ((±)-2-(benzyl-methyl amino) ethyl methyl1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylatemonohydrochloride) is a calcium ion influx inhibitor useful for thetreatment of cardiovascular and cerebrovascular disorders (see, e.g.,U.S. Pat. No. 3,985,758). Nicardipine hydrochloride is currently sold incapsule form and in an injectable intravenous form. The capsule form ismarketed as CARDENE® and is available as an immediate release oralcapsule and as an extended release oral capsule. The injectableintravenous form of CARDENE® is marketed in glass ampuls suitable forintravenous administration following dilution in a compatibleintravenous fluid, such as dextrose or sodium chloride (CARDENE® LV.).Each milliliter of a CARDENE® I.V. ampul contains 2.5 mg nicardipinehydrochloride in water, 48.0 mg sorbitol, buffered to pH 3.5 with 0.525mg citric acid monohydrate and 0.09 mg sodium hydroxide. For infusion,each milliliter of the diluted formulation contains 0.1 mg ofnicardipine hydrochloride, with a variable pH due to the diluentselected by the end user. U.S. Reissue Patent No. RE. 34,618 (a reissueof U.S. Pat. No. 4,880,823) describes an injectable composition ofnicardipine hydrochloride that is stored in a light resistant brownampul. U.S. Pat. No. 5,164,405 describes a buffered pharmaceuticalcomposition containing nicardipine designed for parenteraladministration, that is also stored in an ampul.

The requirement for diluting CARDENE® I.V. before use is associated witha number of disadvantages. One disadvantage is that the diluted solutionis only stable for 24 hours at room temperature. Another disadvantage isthat the pH of the diluted formulation varies depending on the choice ofdiluent. Since CARDENE® I.V. can be used under emergency conditions tocontrol blood pressure, dilution of the concentrated ampul formulationconsumes valuable time that could be used to treat a patient. Otherdisadvantages associated with the dilution step include the potentialfor contamination, dosage errors, and safety hazards associated with theuse of glass ampuls.

The pharmaceutical compositions and methods described herein overcomethese disadvantages. In particular, the ready-to-use, injectableformulations described herein are stable, allow medical personal to useprepared containers containing an injectable formulation off the shelfwithout additional preparation, avoid potential contamination problems,and eliminate dosage errors.

3. SUMMARY

Described herein are ready-to-use, premixed pharmaceutical compositionsof nicardipine or pharmaceutically acceptable salts thereof, which aresuitable for continuous intravenous infusion. By providing ready-to-use,premixed pharmaceutical compositions with a buffered pH, thesepharmaceutical compositions are stable at room temperature for at leastone year. When stored at room temperature, the pharmaceuticalcompositions exhibit between 0% to about 15% loss of drug and between 0%to about 3% (w/w) total impurity formation over an eighteen to twentyfour month period.

Additional benefits of the pre-mixed, ready-to-use, injectablepharmaceutical compositions include convenience and ease of use ascompared to an ampul formulation, improved safety for patients due toelimination of dosage errors and solution contamination, reduction ofmedical waste, and ease of administration in emergency situations.

The present disclosure relates to premixed pharmaceutical compositionscomprising nicardipine or pharmaceutically acceptable salts thereof, oneor more tonicity agents, and a buffer. In some embodiments, thecompositions optionally comprise one or more cosolvents. Nicardipinehydrochloride can be present at concentrations between about 0.05 mg/mlto about 15 mg/ml. Typically, the concentration range for nicardipinehydrochloride is between about 0.1 mg/ml to about 0.2 mg/ml. Optionally,the pharmaceutical compositions can comprise acids and bases.

The pharmaceutical compositions described herein require no dilutionprior to administration and typically have a pH within the range fromabout 3.6 to about 4.7. The compositions can be administered byparenteral routes, including, subcutaneous, intramuscular, intravenous,intra-atrial, or intra-arterial continuous infusion to a patient. Thecompositions are suitable for the short-term treatment of hypertensionwhen oral therapy is not feasible or desirable.

Methods for making a premixed nicardipine hydrochloride formulationsuitable for intravenous administration comprise the steps of providingan effective amount of nicardipine hydrochloride in a solutioncomprising one or more tonicity agents, a buffer, and optionally, one ormore cosolvents. Sufficient water is added to make up the final volume.If required, the pH of the solution can be adjusted using a suitable pHadjuster. The compositions are dispensed in pharmaceutically acceptablecontainers for storage and direct administration to patients.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a diagrammatic illustration of the effect of variousdiluents on the pH and stability of an ampul formulation post dilutionover a twenty four hour period at room temperature.

FIGS. 2A and 2B provide a diagrammatic illustration of the effect of pHon drug loss (FIG. 2A) and total impurity formation (FIG. 2B) in apremixed non-sorbitol formulation comprising 0.1 mg/ml nicardipinehydrochloride, 0.1 mM citric acid and 5% dextrose at 40° C.;

FIGS. 3A and 3B provide a diagrammatic illustration of the effect of pHon drug loss (FIG. 3A) and total impurity formation (FIG. 3B) in apremixed non-sorbitol formulation comprising 0.1 mg/ml nicardipinehydrochloride, 0.1 mM citric acid and 0.9% saline at 40° C.;

FIGS. 4A and 4B provide a diagrammatic illustration of the effect ofnicardipine concentration on impurity formation in non-sorbitol dextroseformulations comprising 0.1 mg/ml nicardipine hydrochloride, 0.1 mMcitrate, 5%dextrose, or 0.2 mg/ml nicardipine hydrochloride, 0.2 mMcitrate and 5% dextrose after six months at 40° C. (FIG. 4A); and, innon-sorbitol saline formulations comprising 0.1 mg/ml nicardipinehydrochloride, 0.1 mM citrate, 0.9% saline, or 0.2 mg/ml nicardipinehydrochloride, 0.2 mM citrate and 0.9% saline after 3 months at 40° C.(FIG. 4B); and

FIGS. 5A and 5B provide a diagrammatic illustration of the effect ofincompatible (FIG. 5A) and compatible (FIG. 5B) plastic film compositionon product stability at 40° C. in a premixed non-sorbitol formulationcomprising 0.2 mg/ml nicardipine HCL, 0.2 mM citric acid, S% dextrose,at a pH of 4.0 to 4.2.

5. DETAILED DESCRIPTION

The premixed pharmaceutical compositions described herein comprisenicardipine or a pharmaceutically acceptable salt thereof as the activeingredient, at least one tonicity agent and a buffer. As used herein,the term “pre-mixed” refers to a pharmaceutical composition that doesnot require reconstitution or dilution before administration to apatient. In contrast to ampul formulations comprising nicardipinehydrochloride that must be diluted prior to use in a diluent andcontainer selected by hospital personnel, the premixed pharmaceuticalcompositions provided herein are stable at room temperature for 6 monthsor longer due to the inclusion of a buffer capable of maintaining the pHwithin an optimal pH range, which is typically between 3.6 to about 4.7.In some embodiments, suitable pH adjusters and/or cosolvents are addedto the pharmaceutical compositions.

5.2 Premixed Pharmaceutical Compositions

The production of stable, ready-to-use, premixed pharmaceuticalcompositions comprising nicardipine and/or its pharmaceuticallyacceptable salts as the active ingredient presents different developmenthurdles than does the development of the concentrated ampul product soldcommercially as CARDENE® I.V. As shown in FIG. 1, the percent ofnicardipine remaining in solution decreases as function of pH over atwenty-four hour period. The percent decrease in nicardipine varies withthe diluent and container chosen by the hospital staff.

As described in the Examples, pH (see, also, e.g., FIGS. 2A, 2B, 3A and3B), the concentration of the active ingredient (see, also, e.g., FIGS.4A and 4B), and the composition of the container material (see, also,e.g., FIGS. 5A and 5B) affect the stability of the active ingredient andthe formation of impurities. Thus, the development of a stable,ready-to-use premixed pharmaceutical composition requires simultaneousoptimization of pH and nicardipine hydrochloride concentration, as wellas selection of a pharmaceutically compatible container. Theready-to-use pharmaceutical compositions described herein exhibit 0% to15% drop in drug concentration and 0% to 3% formation of impurities whenmaintained at room temperature for 6 to at least 24 months. Typically,the pharmaceutical compositions are stable when maintained at roomtemperature for at least 6 months, at least 12 months, at least 18months, and at least 24 months. The compositions are also stable overextended periods of time when maintained at temperatures from about 2°to 8° C. The term “stable”, as used herein, means remaining in a stateor condition that is suitable for administration to a patient.

Compounds for use according to the compositions and methods describedherein that can contain one or more asymmetric centers can occur asracemates, racemic mixtures, and as single enantiomers. Accordingly, thecompositions and methods described herein are meant to comprehend allisomeric forms of such compounds.

The premixed pharmaceutical compositions described herein comprisenicardipine and/or its pharmaceutically acceptable salts. Nicardipine,its pharmaceutically acceptable salts, preparation, and use are known inthe art (see, e.g., U.S. Pat. No. 3,985,758, incorporated herein byreference in its entirety). Examples of pharmaceutically acceptablesalts of nicardipine include hydrochlorides, sulfates, phosphates,acetates, fumarates, maleates and tartrates.

Typically, the premixed pharmaceutical compositions comprise 0.05-15mg/ml nicardipine or a pharmaceutically acceptable salt thereof. Forexample, suitable concentrations of nicardipine or a pharmaceuticallyacceptable salt thereof, include, but are not limited to: 0.05-0.1mg/ml, 0.1-15 mg/ml, 0.1-10 mg/ml, 0.1-5 mg/ml, 0.1-3.0 mg/ml, 0.1-2.0mg/ml, 0.1-1.0 mg/ml, 0.9 mg/ml, 0.8 mg/ml, 0.7 mg/ml, 0.6 mg/ml, 0.5mg/ml, 0.4 mg/ml, 0.3 mg/ml, 0.2 mg/ml or 0.1 mg/ml.

In some embodiments, the premixed pharmaceutical compositions comprisenicardipine hydrochloride as the active ingredient at a concentrationsufficient to permit intravenous administration at a concentrationbetween 0.1 mg/ml to 0.2 mg/ml. In some embodiments, the concentrationof nicardipine hydrochloride suitable for use in the compositions andmethods described herein includes, but is not limited to, at least about0.1 mg/ml. In other embodiments, the concentration of nicardipinehydrochloride suitable for use in the compositions and methods describedherein includes, but is not limited to, at least about 0.2 mg/ml.

In some embodiments, the premixed formulation comprises, in addition tonicardipine and/or its pharmaceutically acceptable salts, a buffer thathas sufficient buffering capacity to maintain the desired pH rangethroughout the shelf-life of the product. As shown in FIGS. 2A and 2B,pH is important for the long term stability of nicardipine in thepremixed pharmaceutical compositions. Although the pH of the premixedpharmaceutical compositions can range from between about 3.0 to about7.0, pharmaceutical compositions having a pH within the range of about3.6 to about 4.7 exhibit a lower percentage of drug degradation andtotal impurities (See FIGS. 2A, 2B, 3A and 3B). Accordingly, suitable pHranges for use in the premixed pharmaceutical compositions include, butare not limited to, pH range of at least about 3.0, at least about 3.1,at least about 3.2, at least about 3.3, at least about 3.4, at leastabout 3.5, at least about 3.6, at least about 3.7, at least about 3.8,at least about 3.9, at least about 4.0, at least about 4.1, at leastabout 4.2, at least about 4.3, at least about 4.4, at least about 4.5,at least about 4.6, at least about 4.7, at least about 4.8, at leastabout 4.9, at least about 5.0, at least about 5.2, at least about 5.5,at least about 6.0, at least about 6.5, at least about 7.0.

In some embodiments, the pH of the premixed pharmaceutical compositionsis between about 3.0 to about 5.0. In other embodiments, the pH of thepremixed pharmaceutical compositions is between about 3.6 to about 4.7.In other embodiments, the pH of the premixed pharmaceutical compositionsis between about 4.0 to about 4.4. In yet other embodiments, the pH ofthe premixed pharmaceutical compositions is 4.2.

Buffers suitable for use in the pharmaceutical compositions describedherein include, but are not limited to, pharmaceutically acceptablesalts and acids of acetate, glutamate, citrate, tartrate, benzoate,lactate, histidine or other amino acids, gluconate, phosphate, malate,succinate, formate, propionate, and carbonate. “Pharmaceuticallyacceptable” is used herein in the sense of being compatible with theother ingredients of the formulation and not deleterious to therecipient thereof. Accordingly, the term “pharmaceutically acceptablesalt” references salt forms of the active compounds which are preparedwith counter ions which are non-toxic under the conditions of use andare compatible with a stable formulation. The concentration of thebuffer in the formulation can be expressed in mg/ml, g/L or as a molarconcentration. In typical embodiments, from about 0.0001 mg/ml to about100 mg/ml of a suitable buffer is present in the pharmaceuticalcompositions. Thus, the premixed pharmaceutical compositions cancomprise from about 0.001 to about 0.01 mg/ml of a suitable buffer, fromabout 0.01 to about 0.01 mg/ml of a suitable buffer, from about 0.01 toabout 0.1 mg/ml of a suitable buffer, from about 0.1 to 1 mg/ml of asuitable buffer, from about 1 to about 5 mg/ml of a suitable buffer,from about 5 to about 10 mg/ml of a suitable buffer, from about 10 toabout 15 mg/ml of a suitable buffer, from about 15 to about 20 mg/ml ofa suitable buffer, from about 20 to about 25 mg/ml of a suitable buffer,from about 25 to about 50 mg/ml of a suitable buffer, from about 50 toabout 75 mg/ml of a suitable buffer, and from about 75 to about 100mg/ml of a suitable buffer.

Alternatively, the buffer concentration can be expressed as molarconcentrations. In typical embodiments, from about 0.1 to 100 mM of asuitable buffer is present in the pharmaceutical compositions. Thus, thepremixed pharmaceutical compositions can comprise a suitable bufferhaving a concentration from about 0.1 to about 100 mM, from about 0.1 toabout 0.5 mM, from about 0.5 to about 1.0 mM, from about 1.0 to about 5mM, from about 5 to about 10 mM, from about I 0 to about 15 mM, fromabout 15 to about 25 mM, from about 25 to about 50 mM, from about 50 toabout 75 mM, and from about 75 to about 100 mM.

In some embodiments, the premixed pharmaceutical compositions furthercomprise a pH adjuster. Suitable pH adjusters typically include at leastan acid or a salt thereof, and/or a base or a salt thereof. Acids andbases can be added on an as needed basis in order to achieve a desiredpH. For example, if the pH is greater than the desired pH, an acid canbe used to lower the pH to the desired pH. Acids suitable for use inpremixed pharmaceutical compositions include, but are not limited to,hydrochloric acid, phosphoric acid, citric acid, ascorbic acid, aceticacid, sulphuric acid, carbonic acid and nitric acid. In someembodiments, hydrochloric acid is used to adjust the pH. By way ofanother example, if the pH is less than the desired pH, a base can beused to adjust the pH to the desired pH. Bases suitable for use inpremixed pharmaceutical compositions include, but are not limited to,sodium hydroxide, potassium hydroxide, calcium hydroxide, sodiumcarbonate, sodium citrate, sodium acetate, and magnesium hydroxide. Insome embodiments, sodium hydroxide is used to adjust to pH.

In some embodiments, the premixed pharmaceutical compositions furthercomprise one or more tonicity agents. Typically, tonicity agents areused to adjust the osmolality of the premixed pharmaceuticalcompositions to bring it closer to the osmotic pressure of body fluids,such as blood or plasma. In some embodiments the tonicity of thepremixed formulation can be modified by adjusting the concentration ofbuffer and/or other components present in the premixed formulation.

Provided that the compositions are physiologically compatible, thecompositions do not require any particular osmolality. Thus, thecompositions can be hypotonic, isotonic or hypertonic. Typically thepremixed pharmaceutical compositions have a tonicity between about 250to about 350 mOsm/kg.

Suitable tonicity agents for use in the premixed pharmaceuticalcompositions include, but are not limited to, anhydrous or hydrous formsof sodium chloride, dextrose, sucrose, xylitol, fructose, glycerol,sorbitol, mannitol, potassium chloride, mannose, calcium chloride,magnesium chloride and other inorganic salts. The quantity of thetonicity agent in the formulation can be expressed in mg/ml or in g/L.In typical embodiments, the tonicity agent(s) is present from about 1mg/ml to about 90 mg/ml. Thus, the premixed pharmaceutical compositionscan comprise one or more tonicity agents at about 1-5 mg/ml, at about5-10 mg/ml, at about 10-15 mg/ml, at about 15-25 mg/ml, at about 25-50mg/ml, at about 50-60 mg/ml, at about 60-70 mg/ml, at about 70-80 mg/ml,and at about 80 to 90 mg/ml, as well as combinations of the aboveranges.

Alternatively, the tonicity agent concentration is measured inweight/volume percent. In typical embodiments, the tonicity agent(s) ispresent from about 0.1% to about 10%. For example, suitable tonicityagent concentrations include, but are not limited to, from about 0.1% toabout 0.2%, from about 0.2% to about 0.3%, from about 0.3% to about0.4%, from about 0.4% to about 0.5%, from about 0.5% to about 0.6%, fromabout 0.6% to about 0.7%, from about 0.7% to about 0.8%, from about 0.8%to about 0.9%, from about 0.9% to about 1%, from about 1% to about 2%,from about 2% to about 3%, from about 3% to about 4%, from about 4% toabout 5%, from about 5% to about 6%, from about 6% to about 7%, fromabout 7% to about 8%, from about 8% to about 9%, and from about 9% toabout 10%, as well as combinations of the above ranges.

In some embodiments, the tonicity agent is dextrose. Typically, theconcentration of dextrose suitable for use in the premixedpharmaceutical compositions is between about 2.5° A (w/v) to about 7.5%.By way of example, suitable dextrose concentrations include, but are notlimited to, from about 2.5% to about 3%, from about 3% to about 3.5%,from about 3.5% to about 4% (which is equivalent to about 40 mg/ml),from about 4% to about 4.5%, from about 4.5% to about 5% (which isequivalent to about 50 mg/ml), from about 5% to about 5.5%, from about5.5% to about 6% (which is equivalent to about 60 mg/ml), from about 6%to about 6.5%, from about 6.5% to about 7%, as well as combinations ofthe above ranges.

In some embodiments, the tonicity agent is sodium chloride. Typically,the concentration of sodium chloride suitable for use in the premixedpharmaceutical compositions is between about 0.1% (w/v) to about 1.8%.By way of example, suitable sodium chloride concentrations include, butare not limited to, from about 0.1% to about 0.2%, from about 0.2% toabout 0.3%, from about 0.3% to about 0.4%, from about 0.4% to about0.5%, from about 0.5% to about 0.6%, from about 0.6% to about 0.7%, fromabout 0.7% to about 0.8% (which is equivalent to 8 mg/ml), from out 0.8%to about 0.9% (which is equivalent to 9 mg/ml), from about 0.9% to about1.0%, from about 1% to about 1.2%, from 1.2% (which is equivalent to 12mg/ml) to about 1.4%, from about 1.4% to about 1.6%, and from about 1.6%to about 1.8%.

In some embodiments, the premixed pharmaceutical compositions comprisetwo, three, four, or more tonicity agents. In these embodiments, theconcentration of each tonicity agent is typically less than theconcentration that is used when only a single agent is present in thepremixed formulation. For example, if the premixed formulation comprisessorbitol at 1.92 mg/ml, a suitable concentration of sodium chloride is8.6 mg/ml. By way of another example, if the premixed formulationcomprises 1.92 mg/ml sorbitol, a suitable concentration of dextrose is48 mg/ml.

In some embodiments, the premixed pharmaceutical compositions furthercomprise one or more cosolvents. A “cosolvent” is a solvent which isadded to the aqueous formulation in a weight amount which is less thanthat of water and assists in the solubilization of nicardipine and/or apharmaceutically acceptable salt thereof, enhances stability of thepremixed formulation, and/or adjusts the osmolality of the premixedpharmaceutical compositions. Cosolvents suitable for use in the premixedpharmaceutical compositions include, but are not limited to, glycols(e.g., polyethylene glycol, propylene glycol), ethanol, and polyhydricalcohols (e.g., sorbitol, mannitol, xylitol).

The quantity of the cosolvent used in the formulation can be expressedin mg/ml or in g/L. In typical embodiments, the cosolvent(s) is presentfrom about 1 mg/ml to about 100 mg/ml. Thus, the premixed pharmaceuticalcompositions can comprise one or more cosolvent(s) at about 1 to about 2mg/ml, at about 2 to about 3 mg/ml, at about 3 to about 4 mg/ml, atabout 4 to about 5 mg/ml, at about 5 to about 10 mg/ml, at about 10 toabout 15 mg/ml, at about 15 to about 25 mg/ml, at about 25 to about 50mg/ml, at about 50 to about 60 mg/ml, at about 60 to about 70 mg/ml, atabout 70 to about 80 mg/ml, at about 80 to 90 mg/ml, and at about 90 to100 mg/ml, as well as combination of the above ranges.

Alternatively, the cosolvent concentration is measured in weight/volumepercent. In typical embodiments, the cosolvent(s) is present from about0.1% to about 25%. For example, suitable cosolvent concentrationsinclude, but are not limited to, at least about 0.1% to 0.3%, from about0.3% to about 0.5%, from about 0.5% to about 0.7%, from about 0.7% toabout 0.9%, from about 0.9% to about 1%, from about 1% to about 3%, fromabout 3% to about 5%, from about 5% to about 7%, from about 7% to about9%, from about 9% to about 11%, from about 11% to about 13% from about13% to about 15%, from about 15% to about 20%, and from about 20% toabout 25%, as well as combination of the above ranges.

In some embodiments, the premixed pharmaceutical compositions furthercomprise one or more cyclodextrins. Due to their structure,cyclodextrins have the ability to form complexes, or inclusioncomplexes, with a variety of organic and inorganic molecules. Complexesof nicardipine with cyclodextrins have been described (see, e.g., U.S.Pat. No. 5,079,237 which describes an inclusion complex of nicardipineor its hydrochloride with alpha-cyclodextrin, beta-cyclodextrin orgamma-cyclodextrin; U.S. Pat. No. 5,519,012 which describes inclusioncomplexes of dihydropyridines, including nicardipine, withhydroxy-alkylated-β-cyclodextrins; and, U.S. Pat. No. 5,904,929 whichdescribes numerous drugs in a pharmaceutical composition with per-C2-18acylated cyclodextrins). None of the above references discloses adihydropyridine in combination with a cyclodextrin comprising a sulfategroup. An example of a commercially available sulfated cyclodextrin isCAPTISOL®. CAPTISOL® is a polyanionic -cyclodextrin derivative with asodium sulfonate salt that is separated from the lipophilic cavity by abutyl ether spacer group, or sulfobutylether. Methods for making thesulfoalkyl ether cyclodextrin derivatives are welllmown in the art andare taught in U.S. Pat. No. 5,376,645. Methods for forming complexes ofthe derivatives with a drug are also welllmown in the art as disclosedin U.S. Pat. No. 5,376,645.

The cyclodextrin concentration can be measured in weight/volume percent.In typical embodiments, cyclodextrin(s) is present from about 0.1% toabout 25%. For example, suitable cyclodextrin(s) concentrations include,but are not limited to, at least about 0.1% to 0.3%, from about 0.3% toabout 0.5%, from about 0.5% to about 0.7%, from about 0.7% to about0.9%, from about 0.9% to about 1%, from about 1% to about 3%, from about3% to about 5%, from about 5% to about 7%, from about 7% to about 9%,from about 9% to about 11%, from about 11% to about 13% from about 13%to about 15%, from about 15% to about 20%, and from about 20% to about25%.

Examples of stable, premixed pharmaceutical compositions comprising theactive ingredient, a tonicity agent, a buffer and optionally, acosolvent are shown in Table 1.

TABLE 1 Tonicity Active Agent(s) Buffer Cosolvent Ingredient (mg/ml)(mg/ml) (mg/ml) pH nicardipine NaCl Citric acid, Sorbitol 3.6-4.7hydrochloride (8.6 mg/ml)  anhydrous (1.92 mg/ml) (0.1 mg/ml) (0.0192mg/ml) nicardipine Dextrose, Citric acid, Sorbitol 3.6-4.7 hydrochloridehydrous anhydrous (1.92 mg/ml) (0.1 mg/ml) (48 mg/ml) (0.0192 mg/ml)nicardipine NaCl Citric acid, None 3.6-4.7 hydrochloride  (9 mg/ml)anhydrous (0.1 mg/ml) (0.0192 mg/ml) nicardipine Dextrose, Citric acid,None 3.6-4.7 hydrochloride hydrous anhydrous (50 mg/ml) (0.0192 mg/ml)nicardipine NaCl Citric acid, None 3.6-4.7 hydrochloride  (9 mg/ml)anhydrous (0.2 mg/ml) (0.0384 mg/ml) nicardipine Dextrose, Citric acid,None 3.6-4.7 hydrochloride hydrous anhydrous (0.2 mg/ml) (50 mg/ml)(0.0384 mg/ml) nicardipine NaCl Citric acid, Sorbitol 3.6-4.7hydrochloride (8.3 mg/ml)  anhydrous (3.84 mg/ml) (0.2 mg/ml) (0.0384mg/ml) nicardipine Dextrose, Citric acid, Sorbitol 3.6-4.7 hydrochloridehydrous anhydrous (3.84 mg/ml) (0.2 mg/ml) (46 mg/ml) (0.0384 mg/ml)

In some embodiments, the pharmaceutical compositions are any asdescribed in U.S. Provisional Application Ser. No. 60/793,084, filedApr. 18, 2006, which is incorporated herein by reference.

5.3 Methods

The order in which various components comprising the compositions isadded to the buffered solution is not critical, provided that theresulting compositions are stable and are suitable for continuousintravenous infusion. Accordingly, the compositions described herein canbe made by prepared in a number of different ways. For example, in someembodiments, the compositions can be prepared by adding buffer, atonicity agent and/or a cosolvent to water; adding nicardipine to thebuffered water solution; adding an pH adjuster to achieve the desiredpH; and then adding sufficient water to make up the final volume. Ifnecessary, the pH can be readjusted to achieve the desired pH range. Byway of another example, the compositions can be prepared by addingbuffer and nicardipine or a pharmaceutically acceptable salt thereof towater; adding a tonicity agent and/or cosolvent, adjusting the pH toachieve the desired pH range; and then adding sufficient water to makeup the final volume. By way of another example, a cosolvent can be addedprior to the addition of nicardipine or a pharmaceutically acceptablesalt thereof, and a tonicity agent can be added after the addition ofnicardipine or a pharmaceutically acceptable salt thereof. By way ofanother example, a tonicity agent can be added prior to the addition ofnicardipine or a pharmaceutically acceptable salt thereof, and acosolvent can be added after the addition of nicardipine or apharmaceutically acceptable salt thereof. By way of another example, thecompositions can be prepared by adding buffer, tonicity agent and/orcosolvent to water; adjusting the pH to a first pH range suitable fordissolving nicardipine (for example, less than pH 3.6); addingnicardipine or a pharmaceutically acceptable salt thereof; adjusting thepH to achieve the desired final pH range; and then adding sufficientwater to make up the final volume.

In some embodiments, pharmaceutical compositions comprising nicardipinehydrochloride, dextrose, and citric buffer at pH 3.6-4.7 can be preparedby adding citric acid to water, adding dextrose to the buffered water,adding nicardipine hydrochloride to the buffered water solution,adjusting the pH if necessary to the range 3.6-4.7, and addingsufficient water to make up the final volume. If necessary, the pH canbe readjusted to between about 3.6 to about 4.7.

In some embodiments, pharmaceutical compositions comprising nicardipinehydrochloride, sodium chloride, and citrate buffer at pH 3.6 to about4.7can be prepared by adding citric acid to water, adding nicardipine tothe buffered water solution, adding sodium chloride to the bufferedwater solution, adjusting the pH to between about 3.6 to about 4.7, andadding sufficient water to make up the final volume. If sorbitol isincluded in the formulation, sorbitol is added at the same time as thecitric acid.

In some embodiments, the pharmaceutical compositions can be prepared byadding nicardipine or a pharmaceutically acceptable salt thereof to anacidic solution having a pH less than 5.0. For example, the acidicsolution can be prepared by adding an acidic component of a buffersystem. A buffer, one or more tonicity agents, and/or cosolvents can beadded to the acidic solution before or after dissolving the nicardipine.Sufficient water is then added to make up the final volume. Ifnecessary, the pH of the composition can be adjusted to between about3.6 to about 4.7.

In some embodiments, the pharmaceutical compositions can be made byadding nicardipine or a pharmaceutically acceptable salt thereof to asolution that has been heated to a temperature greater than 35° C.;adding buffer, one or more tonicity agents, and/or cosolvents to theacidic solutions; and adding sufficient water to make up the finalvolume. If necessary, the pH of the composition can be adjusted tobetween about 3.6 to about 4.7.

The pharmaceutical compositions can be packaged for use in a variety ofcontainers. The compositions are preferably packaged in apharmaceutically acceptable container, such as an intravenous bag orbottles. Due to the light sensitivity of nicardipine, packages can beused that reduce the amount of light which can reach the composition.For example, in some embodiments, the container may, optionally, furthercomprise a light barrier, such as an aluminum overpouch or a carton.

In some embodiments, the premixed pharmaceutical compositions aredispensed in intravenous bags, such as pre-mix bags and admix bags.Intravenous bags are well known in the art and commercially available.Examples of intravenous bags include, but are not limited to: GALAXY®,INTRAVIA®, SOLOMIX®, STEDIM® 71, STEDIM® 100, VIAFLEX®, EXCEL®, VISIV®,VIAFLO™, ADDEASE®, ADD-VANTAGE®, DUPLEX™, FIRST CHOICE™, PROPYFLEX™ andBFS™.

In some embodiments, the components of the bag that come into contactwith the pharmaceutical compositions should not contain polar polymers,such as polyvinyl chloride (PVC) and ethylene vinyl acetate (EVA).Examples of bags that do not contain polar polymers and thus, aresuitable for use in these embodiments, include, but are not limited to,GALAXY®, EXCEL®, VISIV®, and VIAFLO™.

Procedures for filling pharmaceutical compositions in pharmaceuticallyacceptable containers, and their subsequent processing are known in theart. These procedures can be used to produce sterile pharmaceutical drugproducts often required for health care. See, e.g., Center for DrugEvaluation and Research (CDER) and Center for Veterinary Medicine (CVM),“Guidance for Industry for the Submission Documentation forSterilization Process Validation in Applications for Human andVeterinary Drug Products”, (November 1994). Examples of suitableprocedures for producing sterile pharmaceutical drug products include,but are not limited to, terminal moist heat sterilization, ethyleneoxide, radiation (i.e., gamma and electron beam), and aseptic processingtechniques. Any one of these sterilization procedures can be used toproduce the sterile pharmaceutical compositions described herein.

In some embodiments, sterile pharmaceutical compositions can be preparedusing aseptic processing techniques. Sterility is maintained by usingsterile materials and a controlled working environment. All containersand apparatus are sterilized, preferably by heat sterilization, prior tofilling. Then, the container is filled under aseptic conditions, such asby passing the composition through a filter and filling the units.Therefore, the compositions can be sterile filled into a container toavoid the heat stress of terminal sterilization.

In some embodiments, the compositions are terminally sterilized usingmoist heat. Terminal sterilization can be used to destroy all viablemicroorganisms within the final, sealed container containing thepharmaceutical composition. An autoclave is typically used to accomplishterminal heat-sterilization of drug products in their final packaging.Typical autoclave cycles in the pharmaceutical industry to achieveterminal sterilization of the final product are 121° C. for at least 10minutes.

The pharmaceutical compositions described herein can be used forprevention or treatment of acute elevations of blood pressure in a humanpatient in need thereof. In some embodiments, the patients being treatedmay be volume-restricted due to a co-existing medical condition and thuscan benefit from the administration of higher concentration and lowerfluid volume of nicardipine. Examples of medical conditions in which itwould be advantageous to administer low volume formulations include,renal failure, ascites, cerebral edema, congestive heart failure, liverfailure, or a CNS injury. Dosages can be individualized depending uponthe severity of hypertension and the response of the individual patientduring dosing. Typically, the dosage is administered as a continuousinfusion of a pre-mixed product. In some embodiments, the patient has anelevated blood pressure with a systolic equal to or greater than 150 mmHg. In other embodiments, the subject has an elevated blood pressurewith a diastolic value greater than or equal to 90 mm Hg.

In some embodiments, the pharmaceutical compositions can be used toprevent acute elevations of blood pressure associated with variousmedical procedures. Examples of medical procedures associated with acuteelevations of blood pressure include, but are not limited to,electroconvulsive therapy (see, e.g., Avramov, et al., 1998, J. ClinicalAnesthesia, 10:394-400), carotid endarterectomy (see, e.g., Dorman, etal., 2001, J. Clinical Anesthesia, 13:16-19, tracheal intubation (Song,et al., 2001, Anesth Analg., 85:1247-51) and skin incision (Song, etal., 2001, Anesth Analg., 85:1247-51).

In some embodiments, the pharmaceutical compositions can be used totreat acute elevations in blood pressure due to certain cardiovascularand cerebrovascular conditions. Examples of cardiovascular conditionsthat are associated with acute elevations of blood pressure include, butare not limited to, essential hypertension, angina, acute ischemia,systemic arterial hypertension, congestive heart failure, coronaryartery disease, myocardial infarction, cardiac arrhythmias,cardiomyopathies and arteriosclerosis. Examples of cerebrovascularconditions are associated with acute elevations of blood pressureinclude, but are not limited to pulmonary hypertension, cerebralinsufficiency and migraine headache.

In some embodiments, the pharmaceutical compositions can be used totreat other conditions that cause hypertension including, but notlimited to, renal disorders (e.g., renal parenchymal disorders or renalvascular disease), coarctation of the aorta, pheochromocytoma,hyperthyroidism, metabolic syndrome, solid organ transplant anddrug-related hypertension.

In some embodiments, the pharmaceutical compositions can be used toinduce hypotension during surgical procedures including, but not limitedto cardiothoracic surgery, spinal surgeries and head and neck surgeries.

6. Alternative Aspects

In an alternative aspect, the present invention relates to pre-mixed,ready-to-use, injectable pharmaceutical compositions comprising acardiac medication or a pharmaceutically acceptable salt thereof, and atleast one of a co-solvent and a complexing agent, and a buffering agent.The composition may further comprise a tonicity agent. The compositionsare preferably isotonic. The pH of the compositions is preferablybetween 3 and 7. The compositions are preferably packaged in apharmaceutically acceptable container, such as an intravenous bag,syringe or vial. Preferably, the compositions are used for the treatmentof cardiovascular and cerebrovascular conditions. The present inventionalso relates to methods for preparing such compositions. In this otheraspect, the term “pre-mixed”, as used herein, means a pharmaceuticalcomposition that is already mixed from the point of manufacture and doesnot require dilution or further processing before administration. Theterm “pre-mixed” may also mean a pharmaceutical composition wherein theliquid solution and the active pharmaceutical ingredient are separatedfrom the point of manufacture and in storage, such as when the solutionis stored in an intravenous bag and the active pharmaceutical ingredientis lyophilized and stored in a vial that is connected to the bag, butnot in fluid contact with the solution until just before administrationto a patient. Preferably, the pharmaceutical compositions are aqueoussolutions that are administered by injection. Alternatively, thepharmaceutical compositions may be lyophilized and then reconstituted inisotonic saline, for example, before intravenous administration.

In this alternative aspect, the pharmaceutical compositions of thepresent invention comprise a cardiac medication or a pharmaceuticallyacceptable salt thereof. Examples of classes of cardiac medicationsinclude beta-blockers, calcium channel antagonists, angiotensinconverting enzyme inhibitors, diuretics, vasodilators, nitrates,anti-platelet medications and anti-coagulants. Preferably, the cardiacmedication is a calcium channel antagonist or a pharmaceuticallyacceptable salt thereof. More preferably, the cardiac medication is adihydropyridine derivative or a pharmaceutically acceptable saltthereof. Most preferably, the cardiac medication is nicardipine or apharmaceutically acceptable salt thereof. Examples of pharmaceuticallyacceptable salts of nicardipine are hydrochlorides, sulfates,phosphates, acetates, fumarates, maleates and tartarates. The preferredpharmaceutically acceptable salt of nicardipine is nicardipinehydrochloride. The pharmaceutical compositions may comprise 0.05-1.5mg/ml of nicardipine or a pharmaceutically acceptable salt thereof.Preferably, the pharmaceutical compositions comprise 0.15-0.35 mg/ml ofnicardipine or a pharmaceutically acceptable salt thereof. Morepreferably, the compositions comprise 0.2-0.3 mg/ml of nicardipine orpharmaceutically acceptable salt thereof. Nicardipine and itspharmaceutically acceptable salts, their preparation, and their use areknown in the art. For example, they are disclosed in, among otherreferences, U.S. Pat. No. 3,985,758, which is incorporated herein byreference in its entirety.

In some embodiments, the pharmaceutical compositions comprise 0.1-15mg/ml nicardipine or a pharmaceutically acceptable salt thereof. Forexample, suitable concentrations of nicardipine or a pharmaceuticallyacceptable salt thereof, include, but are not limited to: 0.1-15 mg/ml,0.1-10 mg/ml, 0.1-5 mg/ml, 0.1-3.0 mg/ml, 0.1-2.0 mg/ml, 0.1-1.0 mg/ml,0.9 mg/ml, 0.8 mg/ml, 0.7 mg/ml, 0.6 mg/ml, 0.5 mg/ml, 0.4 mg/ml, 0.3mg/ml, 0.2 mg/ml or 0.1 mg/ml.

In this alternative aspect, the pharmaceutical compositions can be usedto treat cardiac conditions. Preferably, the compositions can be used totreat conditions that are alleviated by the administration of calciumchannel antagonists, such as cardiovascular and cerebrovascularconditions. Cardiovascular conditions that can be treated with thepharmaceutical compositions of the present invention include angina,ischemia, systemic arterial hypertension, congestive heart failure,coronary artery disease, myocardial infarction, cardiac arrhythmias,cardiomyopathies and arteriosclerosis. Cerebrovascular conditions thatcan be treated with the pharmaceutical compositions of the presentinvention include pulmonary hypertension, cerebral insufficiency andmigraine. Preferably, the compositions are used to treat hypertension.

In this alternative aspect, the pharmaceutical compositions of thepresent invention also comprise at least one of a cosolvent and acomplexing agent. Therefore, the compositions may comprise a cosolvent,a complexing agent, multiple cosolvents, multiple complexing agents, acosolvent and a complexing agent, a cosolvent and multiple complexingagents, a complexing agent and multiple cosolvents, or multiplecosolvents and multiple complexing agents.

In this alternative aspect, Nicardipine and its pharmaceuticallyacceptable salts are only slightly soluble in water. Cosolvents andcomplexing agents help solubilize nicardipine in the acqueous solutionof the pharmaceutical composition. Cosolvents and complexing agents areespecially beneficial when a high concentration of nicardipine ispresent, such as in the compositions of the present invention. Anadvantage of the compositions of the present invention is that they havea high concentration of nicardipine, which allows the composition to beadministered using a lower volume of intravenous fluid. Suchcompositions can be a treatment option for a greater number of patients,especially volume restricted patients.

In this alternative aspect, patients and medical conditions that maybenefit from a higher concentration and lower fluid volume ofnicardipine include, but are not limited to, the following: acutecongestive cardiac failure; pediatrics; hypertensive crises in elderlypatients where fluid overload is a major concern; all acute stroke areasincluding AIS, ICH and SAH to control blood pressure; controlledhypotension during surgical procedures including cardiothoracic surgery(CABO, coarctation of the aorta, etc.), spinal surgeries, and head andneck surgeries; and neurosurgery for the control of breakthroughhypertension post carotid endarterectomy, traumatic brain injury andpotential treatment of hypertension and vasospasm.

In this alternative aspect, in addition to enhancing solubility,cosolvents and complexing agents enhance the stability of thepharmaceutical compositions. Furthermore, changes may be made to theconcentration of cosolvents and complexing agents in the pharmaceuticalcompositions in order to adjust the tonicity of the pharmaceuticalcompositions. Pharmaceutically acceptable cosolvents are known in theart and are commercially available. Typical cosolvents includepolyethylene glycol (PEG), propylene glycol (PG), ethanol and sorbitol.Preferably, the cosolvent concentration is 0.1-10% weight/volumepercent, which will depend on the pH of the composition. Morepreferably, the cosolvent concentration is 0.1-5%. Most preferably, thecosolvent concentration is 0.1-2%. Preferred cosolvents for thepharmaceutical compositions are propylene glycol and sorbitol.Preferably, the concentration of propylene glycol is 0.1-2%. Morepreferably, the concentration of propylene glycol is 0.1-1%. Mostpreferably, the concentration of propylene glycol is 0.3%. A preferredconcentration of sorbitol is 0.1-2%. An even more preferredconcentration of sorbitol is 0.1-1%. A most preferred concentration ofsorbitol is 0.5%.

In this alternative aspect, pharmaceutically acceptable complexingagents are known in the art and commercially available. Typicalcomplexing agents include cyclodextrins, such as natural cycodextrinsand chemically modified cyclodextrins. Preferably, the complexing agentis a beta cyclodextrin. Preferred complexing agents for thepharmaceutical compositions are 2-hydroxypropyl-j3-cyclodextrin (2HPBCD)and sulfobutylether-j3-cyclodextrin (SBEBCD). Preferably, the complexingagent concentration is 0.1-25% weight/volume percent. More preferably,the complexing agent concentration is 0.1-10%. Most preferably, thecomplexing agent concentration is 0.1-5%. Preferably, the concentrationof 2HPBCD is 15-25%. More preferably, the concentration of 2HPBCD is20-25%. The preferred concentration of SBEBCD is 0.1-10%. An even morepreferred concentration of SBEBCD is 0.1-5%. The most preferredconcentration of SBEBCD is 0.75 to 1%.

In addition, the pharmaceutical compositions in this alternative aspectcan comprise a buffering agent. However, the compositions may comprisemultiple buffering agents. The pharmaceutical compositions of thepresent invention are preferably close to physiological pH in order tominimize the incidence of phlebitis upon administration. However, the pHof the pharmaceutical composition also affects the solubility andstability of nicardipine in the composition. Generally, as the pH of thepharmaceutical composition increases, the aqueous solubility ofnicardipine decreases. As a result, it is difficult to solubilizenicardipine close to physiological pH. In addition, the compositionshould have sufficient buffering capacity such that the solution doesnot precipitate upon dilution with blood when administered.

In this alternative aspect, typical buffering agents include acetate,glutamate, citrate, tartrate, benzoate, lactate, histidine or otheramino acids, gluconate, phosphate and succinate. The preferred bufferingagents are acetate and succinate. A preferred buffering agentconcentration is 1-100 mM. A more preferred buffering agentconcentration is 1-50 mM. An even more preferred buffering agentconcentration is 25-35 mM.

In this alternative aspect, preferably, the pharmaceutical compositionsof the present invention are isotonic, i.e., in the range of270-328mOsm/kg. However, the compositions may have a tonicity in the range of250-350 mOsm/kg. Therefore, the compositions may be either slightlyhypotonic, 250-269 mOsm/kg, or slightly hypertonic, 329-350 mOsm/kg.Preferably, the tonicity of the pharmaceutical compositions is renderedisotonic by adjusting the concentration of any one or more of cosolvent,complexing agent and buffering agent in the solution.

In this alternative aspect, the pharmaceutical compositions of thepresent invention may further comprise a tonicity agent. However, thecompositions may further comprise multiple tonicity agents. Tonicityagents are well known in the art and commercially available. Typicaltonicity agents include sodium chloride and dextrose. A preferredtonicity agent concentration is 1-200 mM. A more preferred tonicityagent concentration is 75-125 mM. An even more preferred tonicity agentconcentration is 90-110 mM.

The pharmaceutical compositions of the present invention are preferablypackaged in pharmaceutically acceptable containers in this alternativeaspect. Pharmaceutically acceptable containers include intravenous bags,bottles, vials, and syringes. Preferred containers include intravenousbags and syringes, which are preferably polymer-based, and vials andintravenous bottles, which are preferably made of glass. It is alsopreferred that the components of the container that come into contactwith the pharmaceutical composition do not contain polyvinylchloride(PVC). The most preferred container is an intravenous bag that does nothave any PVC containing components In contact with the pharmaceuticalcomposition. It is also desirable to protect the pharmaceuticalcompositions from light. Therefore, the container may, optionally,further comprise a light barrier. A preferred light barrier is analuminum overpouch.

This alternative aspect also provides methods as described above forpreparing the pharmaceutical compositions which are sterile.

7. EXAMPLES

Examples 1 through 6 are intended to be illustrative and not limiting asto the general disclosure. Examples 7 through 12 disclose specificembodiments of the pharmaceutical compositions that are principallyillustrative of the alternative aspects described herein.

Examples 1 THROUGH 6 Example 1 Effect of Various Diluents on Stabilityof Concentrated CARDENE®I.V.

Stability results for the concentrated ampul product diluted to 0.1mg/m1 with various commonly used intravenous infusion fluids in an IVbag are shown in FIG. 1. pH after mixing was measured and is reported onthe X-axis. Product stability was measured by monitoring the % drugremaining after duration of 24 hours by RP-HPLC and is shown on theY-axis.

As shown in FIG. 1, the instability of nicardipine hydrochloride isrelated to the increases, for example, a very pronounced drug loss isobtained when the pH is above 4.5. Based on these findings, the productinsert for the marketed ampul product requires product dilution becarried out using specific infusion fluids. Furthermore, the dilutedproduct must be used within 24 hours.

Example 2 Effect of pH on Stability

Stability results for a 0.1 mg/mL nicardipine HCl, 0.1 mM citric acid,and 5% dextrose formulation dispensed in a GALAXY® bag are shown inFIGS. 2A and 2B. Stability results for a 0.1 mg/mL nicardipine HCl, 0.1mM citric acid, 0.9% saline formulation dispensed in a GALAXY® bag areshown in FIGS. 3A and 3B. Stability assessments are done by measuringthe % drug remaining and the total impurity formation as a function oftime using RP-HPLC.

Stability testing was done at an accelerated temperature of 40° C. Basedon published literature, activation energies for drug decompositionsusually fall in the range of 12 to 24 Kcal/mol, with typical value of19-20 Kcal/mol. Under these conditions (assumption Ea=19.4 Kcal/mol) 15weeks storage at 40° C. corresponds to a product with approximately 18months expiration at 25° C. (see, e.g., Connors, K. A., et al., ChemicalStability of Pharmaceuticals, A Handbook for Pharmacists, John Wiley &Sons, 2d ed. 1986).

As shown in FIGS. 2A and 3A, loss in product potency (drop in% drugremaining) due to degradation and adsorption on to the bag surfaceincreased as the formulation pH was increased. For example, after 6months storage at 40° C. for the dextrose formulations, a clear trendindicating increased drug loss for formulations at pH 4.4 and 4.7 can beobserved. At pH 3.3, the drop in% drug remaining is attributed to anincrease in total impurities (FIGS. 2B and 3B), rather than drug lossdue to adsorption. In addition to the observed drug loss, the formationof nicardipine-related impurities (FIGS. 2B and 3B) was also found to bestrongly pH dependent. In this case, however, the reverse trend wasobserved; as the pH was decreased, the total impurities increased.

The results from this study indicate that the formulation pH has asignificant effect on stability of a ready-to-use diluted product. Thefindings of this study indicate that the optimal formulation pH range isbetween about 3.6 to about 4.7. However, depending on the degree ofacceptable drug degradation and/or total impurity formation, other pHranges can be chosen.

Example 3 Effect of Nicardipine Concentration on Impurity Formation

The effect of nicardipine concentration on impurity formation in readyto use premixed compositions comprising 0.1 mg/mL and 0.2 mg/mlnon-sorbitol formulations with dextrose over 6 months at 40° C. is shownin FIG. 4A. The effect of nicardipine concentration on impurityformation in ready to use premixed compositions comprising 0.1 mg/ml and0.2 mg/mL non-sorbitol formulations with saline over 3 months at 40° C.is shown in FIG. 4B. The formulations are dispensed in GALAXY® bags.Stability assessments are done as described in Example 2.

As shown in FIGS. 4A and 4B, in addition to pH, product concentration isanother factor that impacts product stability, in particular theformation of nicardipine-related impurities. The concentrationdependence observed with respect to total impurity formation isminimized as the formulation pH is increased. For example, in FIG. 4Aand B, the effect of concentration is significant at pH 3.3 and isminimized as the pH approaches 4.7.

These results indicate that impurity formation is greater for the 0.1mg/ml formulations as compared to the 0.2 mg/ml formulations for boththe dextrose and saline formulations. Simultaneous optimization of thedrug concentration along with the viable formulation pH range isimportant in the development of ready-to-use premixed drug formulations.

Example 4 Stability Comparison of Sorbitol and Non-Sorbitol Formulations

A stability comparison of sorbitol and non-sorbitol formulations wasconducted under accelerated conditions (4 weeks at 40° C.) using a 0.1mg/mL nicardipine HCI, 1.92 mg/mL sorbitol, 48 mg/mL dextrose, 0.0192mg/mL citric acid, pH 4.2 and a 0.1 mg/mL nicardipine HCI, 50 mg/mLdextrose, 0.0192 mg/mL citric acid, pH 4.0. Both formulations weredispensed in GALAXY® bags. Stability assessments were done by measuringthe % drug remaining and total impurity formation as a function of timeusing RP-HPLC. The results are shown in Tables 2 and 3.

TABLE 2 Dextrose Formulation without Sorbitol % Drug % Total TimeRemaining Impurities 0 100.0 0.08 4 98.1 0.17

TABLE 3 Dextrose Formulation with Sorbitol % Drug % Total Time RemainingImpurities 0 100.0 NMT¹ 0.05 4 96.4 0.13 ¹NMT refers to no more than.

As shown in Tables 2 and 3, minimal differences between the twoformulations were observed in the measured parameters. Based on theseresults, as well as the results shown in Examples 1 and 2, the presenceor absence of sorbitol is not predicted to alter the impact offormulation pH and drug concentration on the stability of the premixedpharmaceutical compositions comprising nicardipine HCl and dextrose orsodium chloride.

Example 5 The Effect of Plastic Film Composition on Stability

The effect of plastic film composition on the stability of ready to usepremixed compositions comprising 0.2 mg/mL nicardipine HCl, 0.2 mMcitrate, 5% dextrose, pH 4.0-4.2 for “incompatible” bags and“compatible” bags is shown in FIGS. 5A and 5B respectively.“Incompatible” bags contain polar polymers, such as polyvinyl chloride(PVC) and ethylene vinyl acetate (EVA). “Compatible” bags do not containpolar polymers.

Stability evaluations were done for the 0.2 mg/mL non-sorbitol dextroseformulation in various commercially available IV infusion bag systems.EXCEL®, VIAFLEX®, VIAFLO™, INTRAVIA®, and VISIV® bags were rinsed inwater and covered with aluminum foil over pouches. The bags were filledwith the above formulation and autoclaved at 105° C. for 21 minutes.STEDIM®71 and GALAXY® bags were aseptically filled with the aboveformulation. Stability assessments were done by measuring the % drugremaining and total impurity formation (data not shown) as a function oftime using RP-HPLC for samples incubated for up to 24 weeks at 40° C.The % drug remaining was calculated relative to the concentrationmeasured post-mixing in tank.

As shown in FIG. 5A, various commercially available IV bags were notcompatible with nicardipine HCI. Significant loss in product potency wasobserved upon storage primarily due to product adsorption in bags thatcontained the polymer PVC (e.g., VIAFLEX® and INTRAVIA®). Nicardipinewas also incompatible with bags containing the polymer ethylene-vinylacetate (EVA) in the contact layer (e.g., STEDIM®71). PVC and EVA areexamples are of polar plastic materials that are incompatible withnicardipine HCl. Because nicardipine HCl is a weak base with a pKa of˜7.2, it is increasingly hydrophobic as the formulation pH increases,and therefore, compatibility with polymeric contact surfaces isdependent on surface charge-related properties.

As shown in FIG. 5B, minimal drop in product potency was observed withcommercial bags comprising copolyester (e.g., EXCEL®), polyethylene(e.g., GALAXY®), and polyolefin blends (e.g., VISIV® and VIAFLO™).

Example 6 Effect of CAPTISOL® on Product Stability

The effect of CAPTISOL® on the stability of ready to use premixedcompositions comprising 0.3 mg/ml Nicardipine, 30 mM NaAcetate, 1.8%Captisol, 112 mM NaCl, pH 4.5 or 0.3 mg/ml Nicardipine, 30 mM NaAcetate,1.8% Captisol, 3.7% Dextrose, pH 4.5 dispensed in 100 ml GALAXY® bagswas monitored for 12 weeks at 5, 25 and 40° C. in (see, e.g., Table 4).Because the drug was stable at 5° C., the data is not shown. Inaddition, the formulations were monitored at 45° C. in 2 mL glass vials(see, e.g., Table 5). All formulations were filled aseptically into thevials and bags by filtering the solution through a 0.22 μm filter.

TABLE 4 % Drug Remaining at 25° C. and 40° C. in GALAXY ® Bag % Drugremaining at 25° C. % Drug remaining at 40° C. Time NaC1 Dextrose NaC1Dextrose (weeks) Formulation Formulation Formulation Formulation 0100.00 100.00 100.00 100.00 1 96.57 99.86 97.15 98.86 2 98.09 100.8097.07 100.40 4 99.45 104.01 98.46 102.56 12 97.23 101.18 95.36 99.00

TABLE 5 % Drug Remaining at 45° C. in Glass Vials % Drug Remaining TimeNaC1 Dextrose (weeks) Formulation Formulation 0 100.00 100.00 2 107.69105.78 4 105.18 105.22 14 102.22 102.80

Pharmaceutical compositions comprising CAPITSOL® exhibited minimal drugloss and impurity formation (data not shown) as a function of time andtemperature. Based on the accelerated stability data at 40° and 45° C.,formulations comprising CAPTISOL®, dextrose or NAC1 should be stable atroom temperature for at least 12 months.

Examples 7 THROUGH 12

Examples 7-12 illustrate experiments performed using specificembodiments. The experiments in Example 7-12 were performed at 45° C. inorder to simulate stressed conditions that cause sufficient productdegradation in a relatively short period of time. Stability comparisonswere done against the control formulation (CF) and/or the commercialproduct formulation (CPF) in order to assess relative differences intheir degradation profiles. The CPF is a marketed drug product and,therefore, degradation behavior of the molecule is well understood as afunction of temperature and time. Stability data are available for themarketed product up to 36 months at room temperature, 22-27° C., and 40°C.

The rationale used in this preliminary screening evaluation is that ifthe degradation kinetics of the evaluated formulation prototypes werecomparable to the CPF at stressed temperatures, drug product stabilitywould likely be comparable or better at room temperature. The currentprototype formulation is stable for at least 18 months at 25° C., andtherefore it is projected that the evaluated formulation prototypes canhave comparable or better stability.

Example 7 Formulation Preparation and Analysis

Appropriate buffers, such as acetate or succinate, containing thedesired cosolvents, such as sorbitol or propylene glycol, and/orcomplexing agents, such as SBEBCD or 2HPBCD, were prepared. Appropriatetonicity agents, such as sodium chloride, were prepared and added tosome of the pharmaceutical compositions. Based upon the finalformulation volume and the target drug concentration, usually 0.2-0.3mg/mL, nicardipine was weighed into an appropriate glass container andprepared buffer was added to dissolve the drug. Tonicity agent, if any,was then added. The solution was then sonicated for up to 45 minutes tofacilitate drug dissolution. Following drug dissolution, the solutionwas filtered through a 0.45 μm syringe filter (Acrodisc LC 13 mm Syringefilter, PVDF Membrane from Life Sciences, PN 4452T). When filtering, thefirst few drops were discarded and the remaining solution was collectedinto another glass container. The prepared formulations weresubsequently dispensed into either vials or intravenous bags.

The following isotonic pharmaceutical compositions were made accordingto the above protocol:

-   -   Pharmaceutical Composition 1 (PC 1): 0.2-0.3 mg/ml nicardipine        hydrochloride, 3.7% sorbitol, and 50 mM Na-acetate, wherein the        pH of the composition is 5.0.    -   Pharmaceutical Composition 2 (PC 2): 0.2-0.3 mg/ml nicardipine        hydrochloride, 1.7% propylene glycol, and 50 mM Na-acetate,        wherein the pH of the composition is 5.0.    -   Pharmaceutical Composition 3 (PC 3): 0.2-0.3 mg/ml nicardipine        hydrochloride, 2.8% sorbitol, and 50 mM Na-succinate, wherein        the pH of the composition is 5.5.    -   Pharmaceutical Composition 4 (PC 4): 0.2-0.3 mg/ml nicardipine        hydrochloride, 1.1% propylene glycol, and 50 mM Na-succinate,        wherein the pH of the composition is 5.5.    -   Pharmaceutical Composition 5 (PC 5): 0.2-0.3 mg/ml nicardipine        hydrochloride, 4.1% sorbitol, and 50 mM Na-acetate, wherein the        pH of the composition is 3.5.    -   Pharmaceutical Composition 6 (PC 6): 0.2-0.3 mg/ml nicardipine        hydrochloride, 1.9% propylene glycol, and 50 mM Na-acetate,        wherein the pH of the composition is 3.5.    -   Pharmaceutical Composition 7 (PC 7): 0.2-0.3 mg/ml nicardipine        hydrochloride, 4.1% sorbitol, and 50 mM Na-acetate, wherein the        pH of the composition is 4.5.    -   Pharmaceutical Composition 8 (PC 8): 0.2-0.3 mg/ml nicardipine        hydrochloride, 1.8% propylene glycol, and 50 mM Na-acetate,        wherein the pH of the composition is 4.5.    -   Pharmaceutical Composition 9 (PC 9): 0.2-0.3 mg/ml nicardipine        hydrochloride, 6.5% sulfobutylether-β-cyclodextrin, and 50 mM        Na-succinate, wherein the pH of the composition is 5.5.    -   Pharmaceutical Composition 10 (PC 10): 0.2-0.3 mg/ml nicardipine        hydrochloride, 6.5% sulfobutylether-β-cyclodextrin, and 50 mM        Na-succinate, wherein the pH of the composition is 6.0.    -   Pharmaceutical Composition 11 (PC 11): 0.2-0.3 mg/ml nicardipine        hydrochloride, 8.5% sulfobutylether-β-cyclodextrin, and 50 mM        Na-succinate, wherein the pH of the composition is 5.5.    -   Pharmaceutical Composition 12 (PC 12): 0.2-0.3 mg/ml nicardipine        hydrochloride, 8.5% sulfobutylether-β-cyclodextrin, and 50 mM        Na-succinate, wherein the pH of the composition is 6.0.    -   Pharmaceutical Composition 13 (PC 13): 0.2-0.3 mg/ml nicardipine        hydrochloride, 8.5% sulfobutylether-β-cyclodextrin, and 50 mM        Na-acetate, wherein the pH of the composition is 5.0.    -   Pharmaceutical Composition 14 (PC 14): 0.2-0.3 mg/ml nicardipine        hydrochloride, 8.5% sulfobutylether-β-cyclodextrin, and 50 mM        Na-citrate, wherein the pH of the composition is 5.5.    -   Pharmaceutical Composition 15 (PC 15): 0.2-0.3 mg/ml nicardipine        hydrochloride, 22.5% 2-hydroxypropyl-β-cyclodextrin, and 50 mM        Na-acetate, wherein the pH of the composition is 5.0.    -   Pharmaceutical Composition 16 (PC 16): 0.2-0.3 mg/ml nicardipine        hydrochloride, 22.5% 2-hydroxypropyl-β-cyclodextrin, and 50 mM        Na-succinate, wherein the pH of the composition is 5.5.    -   Pharmaceutical Composition 17 (PC 17): 0.2-0.3 mg/ml nicardipine        hydrochloride, 17.5% 2-hydroxypropyl-β-cyclodextrin, and 50 mM        Na-acetate, wherein the pH of the composition is 5.0.    -   Pharmaceutical Composition 18 (PC 18): 0.2-0.3 mg/ml nicardipine        hydrochloride, 17.5% 2-hydroxypropyl-βcyclodextrin, and 50 mM        Na-succinate, wherein the pH of the composition is 5.5.    -   Commercial Product (Ampul) Formulation (CPF): 2.5 mg/ml        nicardipine Control Formulation (CF): 0.3 mg/ml nicardipine        hydrochloride, 2.5 mM citrate, and 5% sorbitol, wherein the pH        of the composition is 3.5.    -   Pharmaceutical Composition 19 (PC 19): 0.3 mg/ml nicardipine        hydrochloride, 50 mM sodium acetate, 50 mM sodium citrate, and        50 mM disodium succinate, wherein the pH of the composition is        3.5.    -   Pharmaceutical Composition 20 (PC 20): 0.3 mg/ml nicardipine        hydrochloride, 50 mM sodium acetate, 50 mM sodium citrate, and        50 mM disodium succinate, wherein the pH of the composition is        4.5.    -   Pharmaceutical Composition 21 (PC 21): 0.3 mg/ml nicardipine        hydrochloride, 50 mM sodium acetate, 50 mM sodium citrate, and        50 mM disodium succinate, wherein the pH of the composition is        5.0.    -   Pharmaceutical Composition 22 (PC 22): 0.3 mg/ml nicardipine        hydrochloride, 50 mM sodium acetate, 50 mM sodium citrate, and        25 mM disodium succinate, wherein the pH of the composition is        5.5.    -   Pharmaceutical Composition 23 (PC 23): 0.3 mg/ml nicardipine        hydrochloride, 4.1% sorbitol, and 50 mM sodium acetate, wherein        the pH of the composition is 3.5.    -   Pharmaceutical Composition 24 (PC 24): 0.3 mg/ml nicardipine        hydrochloride, 4.1% sorbitol, and 50 mM sodium acetate, wherein        the pH of the composition is 4.5.    -   Pharmaceutical Composition 25 (PC 25): 0.3 mg/ml nicardipine        hydrochloride, 3.7% sorbitol, and 50 mM sodium acetate, wherein        the pH of the composition is 5.0.    -   Pharmaceutical Composition 26 (PC 26): 0.3 mg/ml nicardipine        hydrochloride, 2.8% sorbitol, and 50 mM sodium acetate, wherein        the pH of the composition is 5.5.    -   Pharmaceutical Composition 27 (PC 27): 0.3 mg/ml nicardipine        hydrochloride, 1.9% propylene glycol, and 50 mM sodium acetate,        wherein the pH of the composition is 3.5.    -   Pharmaceutical Composition 28 (PC 28): 0.3 mg/ml nicardipine        hydrochloride, 1.8% propylene glycol, and 50 mM sodium acetate,        wherein the pH of the composition is 4.5.    -   Pharmaceutical Composition 29 (PC 29): 0.3 mg/ml nicardipine        hydrochloride, 1.7% propylene glycol, and 50 mM sodium acetate,        wherein the pH of the composition is 5.0.    -   Pharmaceutical Composition 30 (PC 30): 0.3 mg/ml nicardipine        hydrochloride, 1.1% propylene glycol, and 50 mM sodium        succinate, wherein the pH of the composition is 5.5.    -   Pharmaceutical Composition 31 (PC 31): 0.3 mg/ml nicardipine        hydrochloride, 6.5% sulfobutylether-β-cyclodextrin, and 50 mM        sodium succinate, wherein the pH of the composition is 5.5.    -   Pharmaceutical Composition 32 (PC 32): 0.3 mg/ml nicardipine        hydrochloride, 6.5% sulfobutylether-β-cyclodextrin, and 50 mM        sodium succinate, wherein the pH of the composition is 6.0.    -   Pharmaceutical Composition 33 (PC 33): 0.3 mg/ml nicardipine        hydrochloride, 22.5% 2-hydroxypropyl-β-cyclodextrin, and 50 mM        sodium acetate, wherein the pH of the composition is 5.0.    -   Pharmaceutical Composition 34 (PC 34): 0.3 mg/ml nicardipine        hydrochloride, 17% 2-hydroxypropyl-β-cyclodextrin, and 50 mM        disodium succinate, wherein the pH of the composition is 5.5.    -   Pharmaceutical Composition 35 (PC 35): 0.3 mg/ml nicardipine        hydrochloride, 0.3% propylene glycol, 0.5% sorbitol, 30 mM        sodium acetate, and 90 mM NaCl, wherein the pH of the        composition is 5.2.    -   Pharmaceutical Composition 36 (PC 36): 0.3 mg/ml nicardipine        hydrochloride, 0.3% propylene glycol, 2.0% sorbitol, 30 mM        sodium acetate, 45 mM NaCl, wherein the pH of the composition is        5.2.    -   Pharmaceutical Composition 37 (PC 37): 1.5 mg/ml nicardipine        hydrochloride, 9% sulfobutylether-β-cyclodextrin, and 30 mM        sodium acetate, wherein the pH of the composition is 4.5.    -   Pharmaceutical Composition 38 (PC 38): 1.5 mg/ml nicardipine        hydrochloride, 9% sulfobutylether-β-cyclodextrin, and 30 mM        sodium acetate, wherein the pH of the composition is 5.0.    -   Pharmaceutical Composition 39 (PC 39): 0.3 mg/ml nicardipine        hydrochloride, and 30 mM sodium acetate, wherein the pH of the        composition is 3.5.    -   Pharmaceutical Composition 40 (PC 40): 0.3 mg/ml nicardipine        hydrochloride, and 30 mM sodium acetate, wherein the pH of the        composition is 4.0.    -   Pharmaceutical Composition 41 (PC 41): 0.3 mg/ml nicardipine        hydrochloride, and 30 mM sodium acetate, wherein the pH of the        composition is 4.5.    -   Pharmaceutical Composition 42 (PC 42): 0.3 mg/ml nicardipine        hydrochloride, 1.8% sulfobutylether-β-cyclodextrin, 30 mM sodium        acetate, and 110 mM NaCl, wherein the pH of the composition is        5.0.    -   Pharmaceutical Composition 43 (PC 43): 0.3 mg/ml nicardipine        hydrochloride, 1.8% sulfobutylether-β-cyclodextrin, 0.3%        propylene glycol, 30 mM sodium acetate, and 85 mM NaCl, wherein        the pH of the composition is 5.0.    -   Pharmaceutical Composition 44 (PC 44): 0.3 mg/ml nicardipine        hydrochloride, 1.8% sulfobutylether-β-cyclodextrin, 30 mM sodium        acetate, and 110 mM NaCl, wherein the pH of the composition is        4.5.    -   Pharmaceutical Composition 45 (PC 45): 0.3 mg/ml nicardipine        hydrochloride, 1.8% sulfobutylether-β-cyclodextrin, 30 mM sodium        acetate, and 200 mM dextrose, wherein the pH of the composition        is 4.5.    -   Pharmaceutical Composition 46 (PC 46): 0.3 mg/ml nicardipine        hydrochloride, 0.75% sulfobutylether-β-cyclodextrin, 30 mM        sodium acetate, and 125 mM NaCl, wherein the pH of the        composition is 4.5.    -   Pharmaceutical Composition 47 (PC 47): 0.3 mg/ml nicardipine        hydrochloride, 1.0% sulfobutylether-β-cyclodextrin, 30 mM sodium        acetate, and 125 mM NaCl, wherein the pH of the composition is        4.5.    -   Pharmaceutical Composition 48 (PC 48): 0.3 mg/ml nicardipine        hydrochloride, 3.4% sorbitol, and 50 mM sodium succinate,        wherein the pH of the composition is 5.6.    -   Pharmaceutical Composition 49 (PC 49): 0.3 mg/ml nicardipine        hydrochloride, 1.3% propylene glycol, and 50 mM sodium acetate,        wherein the pH of the composition is 5.6.    -   Pharmaceutical Composition 50 (PC 50): 0.3 mg/ml nicardipine        hydrochloride, 1.8% sulfobutylether-β-cyclodextrin, 30 mM sodium        acetate, and 110 mM NaCl, wherein the pH of the composition is        5.0.    -   Pharmaceutical Composition 51 (PC 51): 0.3 mg/ml nicardipine        hydrochloride, 0.75% sulfobutylether-β-cyclodextrin, 30 mM        sodium acetate, and 125 mM NaCl, wherein the pH of the        composition is 4.5.    -   Pharmaceutical Composition 52 (PC 52): 0.3 mg/ml nicardipine        hydrochloride, 1.0% sulfobutylether-β-cyclodextrin, 30 mM sodium        acetate, and 125 mM NaCl, wherein the pH of the composition is        4.5.    -   Pharmaceutical Composition 53 (PC 53): 0.3 mg/ml nicardipine        hydrochloride, 0.5% sorbitol, 0.3% propylene glycol, 30 mM        sodium acetate, and 90 mM NaCl, wherein the pH of the        composition is 5.2.    -   Pharmaceutical Composition 54 (PC 54): 0.3 mg/ml nicardipine        hydrochloride, 1.0% sulfobutylether-β-cyclodextrin, 30 mM sodium        acetate, and 125 mM NaCl, wherein the pH of the composition is        4.5.    -   Pharmaceutical Composition 55 (PC 55): 0.3 mg/ml nicardipine        hydrochloride, 0.75% sulfobutylether-β-cyclodextrin, 30 mM        sodium acetate, and 125 mM NaCl, wherein the pH of the        composition is 4.5.    -   Pharmaceutical Composition 56 (PC 56): 0.3 mg/ml nicardipine        hydrochloride, 0.5% sorbitol, 0.3% propylene glycol, 50 mM        sodium acetate, and 90 mM NaCl, wherein the pH of the        composition is 5.2.

The excipient concentration in the control formulation (CF) is identicalto the commercial product formulation (CPF), Cardene® I.V (ampul).However, the concentration of active ingredient in the commercial andcontrol formulations is different. In the commercial product formulation(CPF), the concentration of nicardipine hydrochloride in the ampul is2.5 mg/mL before dilution, and 0.1 mg/ml after dilution with appropriateIV fluids before administration. The control formulation (CF), which isdesigned for premixed ready-to-use intravenous bags such that no furtherdilution with intravenous fluids is required, has a nicardipinehydrochloride concentration of 0.3 mg/mL. The purpose of the controlformulation was to help assess the degradation propensity of theevaluated formulations. Comparable degradation profiles at stressedconditions is indicative of comparable formulation stability.

Example 8 Vial Stability Data with Sorbitol and Propylene GlycolFormulations

The stability in vials of pharmaceutical compositions of the presentinvention comprising a co-solvent and a buffering agent were compared tothe control formulation and the commercial product formulation.Stability was determined by comparing the drug concentration over timefor the below compositions. Specifically, the below compositions wereprepared according to the method in Example 7:

50 mM Na-acetate, pH 3.5. 4.1% sorbitol (PC 5),

50 mM Na-acetate, pH 4.5, 4.1% sorbitol (PC 7),

50 mM Na-acetate, pH 4.5, 1.8% propylene glycol (PC 8),

50 mM Na-acetate, pH 5.0, 3.7% sorbitol (PC 1),

50 mM Na-acetate, pH 5.0, 1.7% propylene glycol (PC 2),

Control formulation: 0.3 mg/mL, 2.5 mM citrate, 5% sorbitol, pH 3.5(CF), and

Commercial product formulation: 2.5 mg/ml, 2.5 mM citrate, 5% sorbitol,pH 3.5 (CPF).

These stability studies were performed in 2 ml glass vials and atelevated temperature conditions, in this case 45° C. Formulationstability was monitored by measuring the drug concentration by RP-HPLCagainst a standard curve. The drug concentration measurements were takenat the start of the experiment, 7 days and 21 days, except for thecommercial product formulation, which measurements were taken at thestart of the experiment and 46 days. These measurements were thenconverted into a percentage in order to show the percentage of drugremaining after a period of time.

Drug Conc. Drug Conc. Drug Conc. (μg/ml) % Drug (μg/ml) % Drug (μ/ml) %Drug PC# t = 0 Remaining t = 7 days Remaining t = 21 days Remaining 5314 100 312 99 289 92 6 302 100 305 101 282 93 7 304 100 303 100 283 938 304 100 304 100 282 93 1 298 100 294 98 274 92 2 290 100 302 104 26491 CF 302 100 301 100 277 92

Drug Conc. Drug Conc. (μg/ml) % Drug (μg/ml) % Drug PC# t = 0 Remainingt = 46 days Remaining CF 2553 100 2265 89

The data show that the stability in vials, drug concentration over time,of the pharmaceutical compositions of the present invention that containco-solvents are comparable to both the control formulation (CF) and thecurrent product formulation (CPF). In addition, the compositions had noadditional degradation products relative to the control formulation(data not shown).

Example 9 Vial Stability Data with SBEBCD Formulations

The stability in vials of pharmaceutical compositions of the presentinvention comprising a complexing agent and a buffering agent werecompared to the control formulation and the commercial productformulation. Stability was determined by comparing the drugconcentration over time for the below compositions. Specifically, thebelow compositions were prepared according to the method in Example 7:

50 mM Na-acetate, 8.5% SBE-beta cyclodextrin, pH 5.0 (PC 13),

50 mM Na-citrate, 8.5% SBE-beta cyclodextrin, pH 5.5 (PC 14),

50 mM Na-succinate, 8.5% SBE-beta cyclodextrin, pH 5.5 (PC 11),

50 mM Na-succinate, 8.5% SBE-beta cyclodextrin, pH 6.0 (PC 12),

Control formulation: 0.3 mg/mL, 2.5 mM citrate, 5% sorbitol, pH 3.5(CF), and

Commercial product formulation: 2.5 mg/ml, 2.5 mM citrate, 5% sorbitol,pH 3.5 (CPF).

These stability studies were performed in 2 ml glass vials and at vialsand at elevated temperature conditions, in this case 45° C. Formulationstability was monitored by measuring the drug concentration by RP-HPLCagainst a standard curve. The drug concentration measurements were takenat the start of the experiment, 6 days, 13 days and 30days, except forthe commercial product formulation, which measurements were taken at thestart of the experiment and 46 days. These measurements were thenconverted into a percentage in order to show a percentage of drugremaining after a period of time.

The data from these stability studies are shown in the following Tables.

[Drug] [Drug] [Drug] [Drug] (μg/ml) % [Drug] (μg/ml) % [Drug] (μg/ml) %[Drug] (μg/ml) % [Drug] PC# t = 0 Remaining t = 6 d Remaining t= 13 dRemaining t = 30 d Remaining 13 381 100 387 101 413 108 390 102 14 334100 339 101 352 105 333 100 11 364 100 378 104 396 109 364 100 12 318100 341 107 355 112 326 103 CF 339 100 352 104 363 107 338 100

Drug Conc. Drug Conc. (μg/ml) % Drug (μg/ml) % Drug PC# t = 0 Remainingt = 46 days Remaining CPF 2553 100 2265 89

The data show that the stability in vials, drug concentration over time,of the pharmaceutical compositions of the present invention that containSBEBCD are comparable to both the control formulation (CF) and thecommercial product formulation (CPF). In addition, the compositions hadno additional degradation products relative to the control formulation(data not shown). It is also worth noting that the target concentrationof 0.2-0.3 mg/mL could be readily attained in the presence ofsulfobutlyether-β-cyclodextrin.

Example 10 Intravenous Bag Stability Data with Sorbitol and PropyleneGlycol Formulations

The stability in intravenous bags of pharmaceutical compositions of thepresent invention comprising a co-solvent and a buffering agent werecompared to a control formulation. Stability was determined by comparingthe drug concentration over time for the below compositions.Specifically, the below compositions were prepared according to themethod in Example 7:

50 mM Na-acetate, pH 3.5. 4.1% sorbitol (PC 5),

50 mM Na-acetate, pH 3.5. 1.9% propylene glycol (PC 6), and

Control formulation: 0.3 mg/mL, 2.5 mM citrate, 5% sorbitol, pH 3.5(CF).

These stability studies were performed in 50 ml intravenous bags and atelevated temperature conditions, in this case 45° C. Formulationstability was monitored by measuring the drug concentration by RP-HPLCagainst a standard curve. The drug concentration measurements were takenat the start of the experiment, 7 days and 21 days. These measurementswere then converted into a percentage in order to show the percentage ofdrug remaining after a period of time.

The data from these stability studies are shown in the Table below.

Drug Conc. Drug Conc. Drug Conc. (μ/ml) % Drug (μ/ml) % Drug (μ/ml) %Drug PC# t = 0 Remaining t = 7 days Remaining t = 21 days Remaining 5314 100 317 101 319 102 6 302 100 311 103 297 98 CF 302 100 276 92 26488

The data show that the stability in intravenous bags, drug concentrationover time, of the pharmaceutical compositions of the present inventionthat contain co-solvents are comparable to the control formulation. Inaddition, the compositions had no additional degradation productsrelative to the control formulation (data not shown). Finally, drugadsorption on the bag surface was minimal at pH 3.5.

Example 11 Intravenous Bag Stability Data with HPCD Formulations

The stability of a pharmaceutical composition of the present inventioncomprising a complexing agent and a buffering agent was evaluated inboth vials and intravenous bags. Stability was determined by comparingthe drug concentration over time for the below composition.Specifically, the below composition was prepared according to the methodin Example 7:

50 mM Na-acetate, pH 5.0, 22.5% HPCD (PC 15).

These stability studies were performed in 50m1 intravenous bags and atelevated temperature conditions, in this case 45° C. The stabilityevaluations were done with a 10 mL fill volume in both the upright andinverted bag configurations. These evaluations were done relative to thesame formulation in a 2 mL glass vial, as a control. Formulationstability was monitored by measuring the drug concentration by RP-HPLCagainst a standard curve. The drug concentration measurements were takenat the start of the experiment, 1 day, 2days, 6days, 9days and 16days.

The data from these stability studies are shown in the Table below.

Drug Drug Drug Drug Drug Drug Conc. Conc. Conc. Conc. Conc. Conc. (μ/ml)(μ/ml) (μ/ml) (μ/ml) (μ/ml) (μ/ml) t = 0 t = 1 day t = 2 days t = 6 dayst = 9 days t = 16 days Vial 271 271 263 260 269 274 Upright 271 266 244264 270 301 Bag Inverted 271 233 203 175 172 150

The data show that the stability, drug concentration over time, of thepharmaceutical composition of the present invention that containscomplexing agent is more promising in the upright configuration of thebag. The data also show that the recovery of drug product was poorer inthe inverted bag configuration.

In order to determine why the composition was more stable in uprightintravenous bags compared to inverted intravenous bags, additionalexperiments were conducted. The drop in drug concentration was not dueto any new degradation product (data not shown). We believe that thedrop in drug concentration was due to drug adsorption on the bagsurface. For many hydrophobic drugs, adsorption on PVC surfaces is acommonly reported concern. Therefore, it is likely that we observedsignificant adsorption in the inverted configuration because the drug isin contact with PVC surfaces. These results suggest the use of non-PVCbags and/or the careful evaluation of the bag size (solution volume) asfeasible options to minimize drug adsorption in order to achieveadequate drug product recovery.

Example 12: Intravenous Bag Stability Data with Sorbitol FormulationsThe stability of a pharmaceutical composition of the present inventioncomprising a cosolvent and a buffering agent was evaluated in both vialsand intravenous bags. Stability was determined by comparing the drugconcentration over time for the below composition. Specifically, thebelow composition was prepared according to the method in Example 7:

50 mM Na-acetate, pH 5.0, 3.7% sorbitol (PC 1).

These stability studies were performed in 50 ml intravenous bags and atelevated temperature conditions, in this case 45° C. The stabilityevaluations were done with both 10 and 50 mL fill volumes in both theupright and inverted bag configurations. These evaluations were donerelative to the same formulation in a 2 mL glass vial, as a control.Formulation stability was monitored by measuring the drug concentrationby RP-HPLC against a standard curve. The drug concentration measurementswere taken at the start of the experiment, 1 day, 2 days, 5 days, 9 daysand 16 days.

The data from these stability studies are shown in the below Table.

Drug Drug Drug Drug Drug Drug Conc. Conc. Conc. Conc. Conc. Conc. (μ/ml)(μ/ml) (μ/ml) (μ/ml) (μ/ml) (μ/ml) t = 0 t = 1 day t = 2 days t = 6 dayst = 9 days t = 16 days Vial 100 102 100 110 104 106 Upright 100 93 89 9885 87 Bag 10 ml Upright 100 98 96 114 97 98 Bag 50 ml Inverted 100 46 4338 21 13 Bag 10 ml Inverted 100 89 87 102 86 85 Bag 50 ml

The data show that the stability, drug concentration over time, of thepharmaceutical composition of the present invention that containscosolvent is more promising in the upright configuration of the bag. Thedata also show that the recovery of drug product was poorer in theinverted bag configuration.

In order to determine why the composition was more stable in uprightintravenous bags compared to inverted intravenous bags, additionalexperiments were conducted. The drop in drug concentration was not dueto any new degradation product (data not shown). We believe that thedrop in drug concentration was due to drug adsorption on the bagsurface. For many hydrophobic drugs, adsorption on PVC surfaces is acommonly reported concern. Therefore, it is likely that we observedsignificant adsorption in the inverted configuration because the drug isin contact with PVC surfaces. This belief is fill configuration relativeto the 50 mL fill configuration, although this poorer recovery may bepartly due to the fact that the 10 mL fill configuration has a highersurface area to volume ratio, which adversely impacts drug adsorptionand recovery. In conclusion, these results suggest the use of non-PVCbags and/or the careful evaluation of the bag size (solution volume) asfeasible options to minimize drug adsorption in order to achieveadequate drug product recovery.

All publications, patents, patent applications and other documents citedin this application are hereby incorporated by reference in theirentireties for all purposes to the same extent as if each individualpublication, patent, patent application or other document wereindividually indicated to be incorporated by reference for all purposes.

While various specific embodiments have been illustrated and described,it will be appreciated that various changes can be made withoutdeparting from the spirit and scope of the invention(s).

1. A method for preventing acute elevations of blood pressure in a humansubject in need thereof, said method comprising parenterallyadministering a pharmaceutical composition for parenteral administrationcomprising: nicardipine or a pharmaceutically acceptable salt thereof; atonicity agent; and a buffer; wherein the composition requires nodilution before administration and has a pH from about 3.6 to about 4.7.2. The method of claim 1, wherein the pharmaceutically acceptable saltis nicardipine hydrochloride.
 3. The method of claim 2, wherein thequantity of nicardipine hydrochloride is in the range from about 0.1 toabout 0.2 mg/ml.
 4. The method of claim 1, wherein the tonicity agent isselected from the group consisting of dextrose and sodium chloride. 5.The method of claim 4, wherein the tonicity agent is dextrose.
 6. Themethod of claim 4, wherein the tonicity agent is sodium chloride.
 7. Themethod according to claim 1, wherein the buffer is citric acid or apharmaceutically acceptable salt thereof.
 8. The method of claim 1,wherein the pharmaceutical composition comprises a cosolvent.
 9. Themethod of claim 8, in which the cosolvent is sorbitol.
 10. The method ofclaim 1, in which the pharmaceutically acceptable salt is nicardipinehydrochloride in a quantity in the range from about 0.1 to about 0.2mg/ml, the tonicity agent is dextrose in a quantity in the range fromabout 46 mg/ml to about 50 mg/ml, and the buffer is citric acid in aquantity in the range of from about 0.0192 mg/ml to about 0.0384 mg/ml.11. The method of claim 10, wherein the pharmaceutical compositioncomprises sorbitol in a quantity in the range of from about 1.92 mg/mlto about 3.84 mg/ml.
 12. The method of claim 1, in which thepharmaceutically acceptable salt is nicardipine hydrochloride in aquantity in the range from about 0.1 to about 0.2 mg/ml, the tonicityagent is sodium chloride in a quantity in the range of from about 8.3mg/ml to about 9 mg/ml, and the buffer is citric acid in a quantity inthe range of from about 0.0192 mg/ml to about 0.0384 mg/ml.
 13. Themethod of claim 12, wherein the pharmaceutical composition comprisessorbitol in a quantity in the range of from about 1.92 mg/ml to about3.84 mg/ml.
 14. The method of claim 1, wherein the pharmaceuticalcomposition comprises a pH adjuster selected from the group consistingof an acid and a base.
 15. The method of claim 1, wherein the osmolalityof the is in the range from about 250 to 350 mOsm/kg.
 16. The method ofclaim 1, wherein the pharmaceutical composition comprises apharmaceutically acceptable container selected from the group consistingof intravenous bags and bottles. 17-39. (canceled)